KRAS belongs to the RAS family of proteins with a molecular weight of about 21 kDa and GTP hydrolytic activity. KRAS is found inside the cell membrane, and has a role to transmit signals into cells in response to the binding of extracellular growth factors such as Epidermal Growth Factor (EGF) with the receptors. Activating mutations can be found in KRAS, and they are found in about 20% of human cancer. The frequency of the occurrence of KRAS activating mutations is high particularly in pancreatic cancer, colon cancer, and lung cancer (see “Cancer Res”, Vol. 72, p. 2457, 2012). There is a report that anti-epidermal growth factor receptor (EGFR) antibody drugs: cetuximab and panitumumab are ineffective in colon cancer patients with KRAS activating mutations (see “N Engl J Med”, Vol. 360, p. 1408, 2009; “J Clin Oncol”, Vol. 26, p. 374, 2008; “J Clin Oncol”, Vol. 26, p. 1626, 2008). KRAS has been regarded as a desirable target of anticancer drugs, and there have been long-standing attempts to discover KRAS inhibitors by a low-molecular drug discovery approach (see “Cancer Biology & Therapy”, Vol. 1, p. 599, 2002). However, there is no effective therapeutic agent for treating a cancer etc. that targets the KRAS.
As a method of suppressing the expression of a target gene, for example, a method utilizing RNA interference (hereinafter referred to as RNAi) and the like are known, and specifically, a phenomenon in which when a double-stranded RNA having a sequence identical to that of a target gene is introduced into Nematoda, the expression of the target gene is specifically suppressed has been reported (see “Nature”, Vol. 391, No. 6669, pp. 806-811, 1998). Further, it has been found that even when a double-stranded RNA having a length of 21 to 23 bases is introduced into Drosophila, instead of a long double-stranded RNA, the expression of a target gene is suppressed. This is named a short interfering RNA (siRNA) (see International Publication No. WO 01/75164).
RNAi has been frequently verified also in in vivo tests. The effect of siRNA with a length of 50 base pairs or less on fetal animals (see United States Patent Application Publication No. US 2002-132788) and the effect thereof on adult mice (see International Publication No. WO 03/10180) are reported. Moreover, the effect of suppressing the expression of a specific gene has been found in each of organs that are kidney, spleen, lung, pancreas, and liver when siRNA is intravenously administered to a fetal mouse (see “Nature Genetics”, Vol. 32, No. 1, pp. 107-108, 2002). Furthermore, it has been reported that also when siRNA is directly administered to brain cells, the expression of a specific gene is suppressed (see “Nature Biotechnology”, Vol. 20, No. 10, pp. 1006-1010, 2002).
KRAS siRNA is described in, for example, Patent Document 1, Patent Document 2, etc.
Medicines containing an siRNA are described in, for example, Patent Document 3, Patent Document 4, Patent Document 5, etc.
Patent Document 3 discloses medicines containing an siRNA and, for example, 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA) etc. DLinDMA etc. are characterized in that for the purpose of developing more flexible cationic lipids, thereby increasing the membrane fluidity of a liposome or the like, the higher alkyl groups of N-(2,3-di-(9-(Z)-octadecenoyloxy))-propan-1-yl-N,N,N-trimethylammonium chloride (DOTAP) and N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA) that are structurally analogous cationic lipids thereto are replaced by higher alkyl groups containing at least two sites of unsaturation. In addition, Patent Document 4 discloses medicines containing an siRNA and, for example, 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA) etc.
In addition, Patent Document 5 discloses, for example, trans-3,4-bis(((Z)-octadeca-9-enoyloxy)methyl)pyrrolidine (Compound I-3) etc.